Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)
| العنوان: | Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601) |
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| المؤلفون: | Shayn M. Peirce, Matthew J. Lazzara, Kenny M. Hansson, Maria Wågberg, Peter Gennemark, Regina Fritsche-Danielson, Joachim Almquist, S. Michaela Rikard, Anthony C. Bruce, Paul J. Myers |
| المصدر: | Cellular and Molecular Bioengineering |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Angiogenesis, VEGF receptors, General Biochemistry, Genetics and Molecular Biology, Diabetic ulcers, Pharmaceutical Sciences, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, In vivo, Distribution (pharmacology), Medicine, Chronic wounds, Messenger RNA, integumentary system, biology, business.industry, Computational modeling, Farmaceutiska vetenskaper, Partial differential equations, 030104 developmental biology, Modeling and Simulation, Drug delivery, Diabetic wound healing, biology.protein, Original Article, Wound healing, business, 030217 neurology & neurosurgery, Biomedical engineering |
| الوصف: | Introduction Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing. Methods We modified a previously published model of cutaneous wound healing based on coupled partial differential equations that describe the density of sprouting capillary tips, chemoattractant concentration, and density of blood vessels in a circular wound. Key model parameters identified by a sensitivity analysis were fit to data obtained from an in vivo wound healing study performed in the dorsum of diabetic mice, and a pharmacokinetic model was used to simulate mRNA and VEGF-A distribution following injections with AZD8601. Due to the limited availability of data regarding the spatial distribution of AZD8601 in the wound bed, we performed simulations with perturbations to the location of injections and diffusion coefficient of mRNA to understand the impact of these spatial parameters on wound healing. Results When simulating injections delivered at the wound border, the model predicted that injections delivered on day 0 were more effective in accelerating wound healing than injections delivered at later time points. When the location of the injection was varied throughout the wound space, the model predicted that healing could be accelerated by delivering injections a distance of 1-2 mm inside the wound bed when compared to injections delivered on the same day at the wound border. Perturbations to the diffusivity of mRNA predicted that restricting diffusion of mRNA delayed wound healing by creating an accumulation of VEGF-A at the wound border. Alternatively, a high mRNA diffusivity had no effect on wound healing compared to a simulation with vehicle injection due to the rapid loss of mRNA at the wound border to surrounding tissue. Conclusions These findings highlight the critical need to consider the location of drug delivery and diffusivity of the drug, parameters not typically explored in pre-clinical experiments, when designing and testing drugs for treating diabetic wounds. Funding Agencies|AstraZenecaAstraZeneca; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [HL116449, HL137755, AR069393, EY028868, T32LM012416]; National Science FoundationNational Science Foundation (NSF) [1842490, 1716537]; Allen Discovery Center at Stanford University |
| وصف الملف: | application/pdf |
| تدمد: | 1865-5033 1865-5025 |
| DOI: | 10.1007/s12195-021-00678-9 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14e3fd9c39497ac4bfbe62b3900a8d99 https://doi.org/10.1007/s12195-021-00678-9 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....14e3fd9c39497ac4bfbe62b3900a8d99 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18655033 18655025 |
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| DOI: | 10.1007/s12195-021-00678-9 |